Ventricular pacing in cardiac-related applications

ABSTRACT

Various aspects of the present disclosure are directed toward an asynchrony index that is related to data of a subject&#39;s heart. The asynchrony index includes intra-ventricular or inter-ventricular electrical asynchrony data. The intra-ventricular or inter-ventricular electrical asynchrony data can be specific to a certain subject, and indicative of a different conditions specific to that subject.

RELATED DOCUMENTS

This patent document claims benefit under 35 U.S.C. §119 to U.S.Provisional Patent Application Ser. No. 61/708,992, entitled“Ventricular Pacing in Cardiac-Related Applications” and filed on Oct.2, 2012, which, along with the Appendices and any cited referencestherein, is fully incorporated herein by reference.

SUMMARY

Various aspects of the present disclosure are directed toward use of anasynchrony index that is related to data of a subject's heart, forinstance, in which the asynchrony index relates to or includesintra-ventricular or inter-ventricular electrical asynchrony data, anddata associated with cardiac/physiological conditions. Theintra-ventricular or inter-ventricular electrical asynchrony data can bespecific to a certain subject, and indicative of different conditionsspecific to that subject. As discussed below, the asynchrony indexprovides data sets for the different subject-specific conditions,spanning a range of uses and implementations.

In certain embodiments, apparatuses and methods are directed toward usewith a subject's cardiac data, corresponding to an electrocardiogram(ECG) or pseudo-surface ECG. The apparatuses include a first and/orsecond circuit that store an asynchrony index in which sets ofintra-ventricular or inter-ventricular electrical asynchrony data areprovided for the subject's heart. The sets respectively correspond todifferent conditions that are specific to the subject. Additionally, thefirst and/or second circuits provide access to at least one of the setsof intra-ventricular or inter-ventricular electrical asynchrony data.This occurs in response to an input signal that targets a specificportion of the asynchrony index or otherwise identifies one of thedifferent conditions that are specific to the subject (or acorresponding one of the sets of intra-ventricular or inter-ventricularelectrical asynchrony data). In one method relating thereto, a subject'scardiac data (corresponding to an electrocardiogram (ECG) orpseudo-surface ECG) is collected and organized, e.g., in the form of atable, with sets of intra-ventricular or inter-ventricular electricalasynchrony data that are specific to the subject's heart; the collectedand organized cardiac data can also include and/or be correlated todifferent conditions that are specific to the subject.

Certain other embodiments of the present disclosure are directed towardapparatuses and methods that include an acquisition circuit thatcollects a first signal at a first location of a subject's heart and asecond signal at a second location of the subject's heart. The firstsignal is indicative of at least one of a first heart surfaceelectrocardiography (ECG) and a first intracardiac electrogram (EG). Thesecond signal is indicative of at least one of a second heart surfaceECG and a second intracardiac electrogram (EG). The apparatuses alsoinclude preprocessing circuitry that performs detection and filtering ofQRS complexes of the first signal and the second signal collected by theacquisition circuit. Further, the apparatuses include analysis circuitrythat extracts signal information including parameters or data pointsfrom the first signal and the second signal. Additionally, the analysiscircuitry segments the QRS complexes of the first signal and the secondsignal using the extracted information. Further, the analysis circuitrycross-correlates the QRS complex segments of the first signal and thesecond signal to produce a correlation signal, and provides orcalculates an asynchrony index that is based on or corresponds to thecorrelation signal and that indicates a level of electrical asynchronybetween the first location and the second location.

Yet other embodiments are directed toward various methods for using andgenerating asynchrony index data as described in connection with one ormore of the above apparatuses and/or methods of use.

Aspects of the present disclosure are also directed toward a dedicateddevice to assess the degree of inter and intra-ventricular electricalasynchrony (IEA) to determine the need for resynchronization therapy.Further, various aspects of the present disclosure are directed towardevaluation, during the implant procedure, to determine the correctlocation of the stimulation lead(s), and the optimization of the postimplant outcome, non-invasively using two or more leads of the surfaceECG. Moreover, certain aspects of the present disclosure are directedtoward finding and initially programming into the device, the optimumatrio-ventricular interval that minimizes IEA, and finding and initiallyprogramming the interventricular interval that minimizes IEA in singleand/or multiventricular stimulation systems.

Various aspects of the present disclosure are also directed toward adevice and process that allows the continuous optimization of theauriculo ventricular interval and the inter ventricular interval inmultichamber and/or multisite stimulation devices by reprogramming thoseparameters using electrocardiograms derived from intracardiac ECGs usinga combination of the stimulation electrodes with the stimulation device.Other aspects of the present invention are directed toward the chronicoptimization of the atrio-ventricular interval and the inter ventricularinterval in multichamber and/or multisite stimulation devices bycommunicating automatically with the programmer and then reprogrammingthe device automatically, or with medical personnel intervention, toconfirm/approve the new settings recommended by the optimizationprocess, with this process taking place either at each follow up visitor at the home of the patient through a remote patient monitoring and/ormanagement system. The invention also describes the use of the samemethod to optimize the lead position and initial atrioventricular delayin patients who are undergoing a right ventricular only implantation ofa pacemaker. In still other aspects of this invention it describes amethod and apparatus that allows the optimization of theatrio-ventricular interval and the inter ventricular interval (VV) inmultichamber and/or multisite stimulation devices by communicatingautomatically with the programmer and then reprogramming the deviceautomatically or with medical personnel intervention to confirm/approvethe new settings recommended by the optimization process, with thisprocess taking place either at each follow up visit or at the home ofthe patient through a remote patient monitoring and/or managementsystem.

INTRODUCTION

Pacing in right ventricular apex causes intra and inter ventricularelectrical asynchrony (IEA) in roughly fifty percent of the patientsthat are paced in the right ventricle. Naturally occurring left bundlebranch block (LBBB) also deteriorates ventricular function by creating,in many instances, an even worse type of ventricular asynchrony than RVapex pacing. IEA has been associated in the literature with anacceleration in the progression of heart failure and/or with a higherlikelihood of developing heart failure (HF). With the idea of improvingelectrical asynchrony, especially in patients with heart failure, inrecent years two lines of research have been pursued, one of them triesto resynchronize both ventricles, placing an additional catheter throughthe coronary sinus to stimulate the right ventricle (RV) and leftventricle (LV) in a coordinated fashion (Biventricular Pacing BVP, alsocalled cardiac resynchronization therapy or CRT). BVP has been linkedmostly to patients with Heart Failure and IEA. Due to the high expense,complexity and risk of BVP, it has not been widely utilized to preventthe IEA that is created by RV apex pacing in pacemaker patients that arenot otherwise indicated for BVP. Thus, the second line of research,which has remained focused on the simpler approach of stimulating theinterventricular septum, tries to achieve a more normal activation ofthe heart and, targets both patients with narrow and wide QRS complexthat are indicated for a regular single or dual chamber pacemakerimplant.

There are four types of pacemakers: (1) asynchronous; (2) single-chambersynchronous; (3) double-chamber AV sequential; and (4) programmable.Asynchronous (AOO, VOO, DOO) pacemakers discharge at a preset rate thatis independent of a patient's (inherent) heart rate. Single-chambersynchronous (AAI, VVI) pacemakers discharge at a preset rate only when apatient's (spontaneous) heart rate drops below the preset rate.Dual-chamber AV sequential pacing (VDD, DVI, DDD) pacemakers usually usetwo electrodes: one in the atrial appendage and one in the rightventricular apex. The atrium is stimulated to contract first, then afteran adjustable AV atrio-ventricular (AV) interval, the ventricle isstimulated. Programmable pacemakers have programmable features such aspacing rate, pulse duration, voltage output, and R-wave sensitivity,atrial tachycardia management features, atrial and sometimes ventricularantitachycardia pacing features, (programmable AV delays, dynamic AVdelays, pulse width, automatic lead mode switching, etc.)

All of these types of pacemakers can be fitted with high voltage outputand/or especial waveforms, like those discussed by U.S. Pat. Nos.7,512,440; 8,005,544; 8,014,861; and 8,050,756; and U.S. PatentPublication No. 2012/0101539, in the right ventricular channel torestore a normal activation sequence by bypassing the conduction systemblock by pacing in the His bundle, in the right ventricular (RV) septumeither in its right ventricular or right atrial portions. For simplicitywe will call this type of high voltage/especial waveform His bundletherapy XSTIM in the rest of this disclosure.

Resynchronization therapy (CRT) and XSTIM aim to improve the heart's IEAby correcting this problem so as to improve cardiac function. Most ofthe information used to understand the benefits of CRT and XSTIM hasbeen derived either from acute measurements of arterial pressures, andthe rate of change of intraventricular pressures, or from outcome trialsthat assessed the mortality and hospitalization rate that theapplication of this therapy had on heart failure (HF) patients. Outcomesinformation, even though critical to understanding the actual clinicalbenefit of a therapy has not provided any information about the actualsuccess of CRT in correcting the underlying problem for a given patient,it only provides the likely outcome for a population of patients.Hemodynamic information, although accurate in measuring the mechanicaleffects of CRT and XSTIM when they attempt to correct the underlyingelectrical asynchrony problem, is only a surrogate variable, since itdoes not provide corroborative information about the effectiveness ofCRT or XSTIM in correcting the electrical asynchrony, currently thoughtto be the core problem creating the asynchrony. Furthermore, previousindications for the application of CRT do not require the prescribingphysician to verify that the patient actually has mechanical asynchronyto start with. Because of this, aspects of the present disclosureemphasize the diagnostic evaluation of IEA and its optimization, bothinitially and post-implant, by an electrical method, through theparameters derived from electrical activity of the heart that is moreaccurate than the simple QRS width measurement required to determine thepresence of LBBB, as is currently required by CRT's present clinicalindication (http://www.theheart.org/article/1122825.do).

Prior to the implantation of a CRT device or a right ventricular pacingdevice, some patients have left bundle branch block (LBBB), arequirement for CRT's indication but not for right ventricular pacing.In general, the LBBB is accompanied by electrical and mechanicalasynchrony, but its extent is not measurable with the surface ECG.Therefore, at this stage, previously developed techniques do not providethe prescribing physician or the implanting physician with any method todetermine if the patient actually has asynchrony that could be correctedby implanting a CRT device. Additionally, previously developedtechniques do not provide the implanting physician with any simpletechnique to determine whether the site chosen for stimulation is eithercorrecting the electrical and mechanical asynchrony, as should be thecase after a CRT implant, or not creating electrical and mechanicalasynchrony during pacing after the implantation of a right ventricula,and/or a CRT pacing device. The asynchrony level could be worse duringpacing than at the previous baseline in the particular patient underconsideration for the implant site and/or sites chosen and/or availablefor fixating the lead and/or leads. For instance, all the studies doneto prove the benefits of CRT are population based studies where mostbenefited but some did not. Further, previously developed techniques donot provide the implanting physician with any simple method to evaluatethe optimum (from a reduction or avoidance of asynchrony point of view)atrio-ventricular (AV) delay or interventricular (VV) delay. Similarly,after the implantation, previously developed techniques do not providethe follow-up physician any simple method to confirm that the implantedCRT device is working correctly and is correcting the baselineasynchrony that caused the prescription of the device in the firstplace.

Previously developed techniques only allow the follow-up physician toknow that the biventricular pacing (BVP) device is pacing in bothchambers and capturing in both, but not whether or not the underlyingIEA that caused the prescription of the BVP device has been corrected bythe device. The only method available to the follow-up physician is toassess the degree of success through the visualization or narrowing ofthe QRS with a conventional ECG. This method, however, does not provideenough information to know if the left ventricle (LV) is asynchronous,or not, especially when the narrowing of ECG QRS is not marked as itoccurs in most cases of CRT.

In cases of patients with a narrow QRS in need of a pacemaker, pacingwill most likely widen the QRS, since any artificial stimulation will beworse than normal conduction, unless a method like XSTIM is used.However, this should be checked in order to determine the best implantsite in the right ventricle such that the artificial stimulation createdby pacing can be verified to either not worsen the intraventricularsynchrony that existed before the pacemaker implant or to produce atherapeutically tolerable level of asynchrony, for the particularpatient under treatment. Currently no such check is done and the rightventricular pacing lead is placed in the right ventricle withoutchecking for the effect of pacing site on IEA in most centers. Thereason IEA is not checked is that there are no simple easy to use, quickand inexpensive methods that allow for its evaluation.

Finally, after implantation, each patient needs specific programmingadjustments, both at discharge and follow-up appointments to maintainthe optimum level of asynchrony as his/her heart substrate is changingin adaptation to the new modality of electrical activation created bythe stimulation therapy or to changes in the patient's drug regimen.Aspects of the present disclosure solve the aforementioned issues byproviding the prescribing physician a simple non-invasive method toconfirm the existence of asynchrony before recommending the implant of aCRT or XSYNC device, by allowing the implanting physician to select theoptimum pacing sites that provide a therapeutically acceptable level ofelectrical asynchrony, and by allowing the discharge physician toprogram an initial atrio-ventricular and interventricular delay thatensure that the level of asynchrony is below the therapeutic target forthe patient being treated. Additionally, aspects of the presentdisclosure solve the aforementioned issues by providing simple means tothe referring physician to confirm that the electrical asynchrony thatcreated the need for the referral for a CRT device has been improved bythe device to his/her therapeutic target, and by also providing thestandard pacemaker implanting physician the means to select a pacingsite in the right ventricle that does not worsen electrical asynchronyabove the therapeutic target he or she has after a regular rightventricular pacemaker is implanted. Further, aspects of the presentdisclosure utilize the intracardiac electrodes used for cardiacstimulation and/or the can of the stimulation device and/or anyindifferent electrodes it may have to derive a pseudo-surfaceelectrocardiogram (ECG) to be used as input data to evaluate the levelof IEA. This type of ECG has the added advantage that allows thestimulation device to continuously change the atrio-ventricular delayand the interventricular delay (every second, every minute, every hoursor as the follow up physician programs into the device) to optimize thepacing parameters to maintain asynchrony below the therapeutic target.To accomplish these goals, aspects of the present disclosure utilizeeither the surface ECG signals (or a pseudo ECG, derived fromintracardiac signals) to compute an Intraventricular ElectricalAsynchrony Index (IEAI).

Previously developed methods utilize several processes for evaluatingthe electro-mechanical asynchrony, one of them is ultrasoundechocardiography. Within the ultrasound group, tissue Doppler Imaging(TDI) is the most common method used for measuring asynchrony.Ultrasound methods are highly inaccurate and imprecise due to thetwisting motion of the heart wall during contraction (which only complexset ups account for, since different layers of tissue will move atdifferent times, making the interpretation of asynchrony measurementsvery difficult). They are very expensive and time consuming and out ofthe realm of what the referring, follow-up and implanting physicians canhave reasonable access to. Lack of knowledge and understanding of thisfactors has led to the proliferation of inaccurate methods for assessingasynchrony based on echocardiography and Doppler Tissue imaging with theconsequence that none has been adopted as a clinical standard, leavingthe implanting and follow up physician without a tool to use in theassessment of whether the therapeutic level of asynchrony prescribed hasbeen reached or not. Furthermore, if during the implantation of a devicethe presence of echocardiographic recording systems is added, complexityis also added to the procedure, which increases the surgical time andthereby increases the cost of the procedure and the risk of infection.The time it takes to perform a relatively accurate ultrasonic evaluationof a single set of parameters on their impact in asynchrony levels is inthe order of minutes. Aspects of the present disclosure would decreasethat time to the order of seconds. Finally, given that the root cause ofthe degradation that is being corrected is the electrical conductionsystem of the heart, direct measurements of the effect of the therapy onthat conduction is the best strategy for determining the success of thetherapy, and not the measurement of secondary surrogate mechanicalvariables that them, themselves are very prone to measurement errors andmiss-interpretation of their meaning.

Aspects of present invention will provide significant cost savings tothe Health Care system that adopts them, since currently outcome basedmethods used to determine success of this therapy actually implantpeople that may not receive any benefit, but just belong to astatistically derived population or group or subset of the universe ofpatients that have a high likelihood of deriving benefit from thetherapy when the lead position is not optimized. Furthermore, it isperfectly conceivable that subgroups inside the previously referred tosubgroup could be worsened by the therapy since electrical stimulationcould either be worsening electrical asynchrony in those who despiteshowing LBBB didn't have significant IEA or those whose lead position issuch that it ends up worsening IEA from its baseline level. At the sametime the present invention will provide significant benefit to societyby enabling physicians to only treat those who need to be treated, andby providing inexpensive easy to use and quick tools for physicians tomake sure that they are not only improving those patients whom theyimplant but that they are delivering no harm to any of them, includingthe patients that require pacing for reasons other than IEA and in whomthe correction of their problem, requiring ventricular pacing, could beinadvertently triggering IEA and either increasing their probability ofdeveloping heart failure or if they already had it, accelerating itsprogression.

The above discussion is not intended to describe each embodiment orevery implementation. The figures and following description alsoexemplify various embodiments.

BRIEF DESCRIPTION OF THE FIGURES

Various example embodiments may be more completely understood inconsideration of the following detailed description in connection withthe accompanying drawings, in which:

FIG. 1 shows an example block diagram of the acquisition system ofsignals (His and arterial pulse are optional), consistent with variousaspects of the present disclosure;

FIG. 2 shows an example block diagram of electrocardiogram signalpreprocessing, consistent with various aspects of the presentdisclosure;

FIG. 3 shows an example block diagram of an analysis block, consistentwith various aspects of the present disclosure;

FIG. 4 shows an example actual calculation of parameters T_(shift) andX_(corrwidth) from the D1−D2 cross-correlation signal, and SP1, inaccordance with various aspects of the present disclosure.

FIGS. 5A-5B show validation of various aspects of the asynchrony index(IEAI) as described in the present invention, versus apreviously-developed technique by showing the correlation between TissueDoppler Imaging (TDI) and Coronary Sinus latency (CS) versus the IEAI;

FIG. 6A shows a block diagram of an example workflow during a rightventricular (RV) pacing device implantation to help the implantersdecide where to fix the right ventricular lead, utilizing variousaspects of the present disclosure (the tries counter has been obviatedfor simplicity, in the apical lead position side (left));

FIG. 6B shows a block diagram of an example workflow during aBi-ventricular pacing device implantation, utilizing various aspects ofthe present disclosure;

FIG. 6C shows a block diagram of an example workflow (sites testedcounter obviated for simplicity reasons in the apical lead position side(left)) during a right ventricular pacing upgrade device implantation,utilizing various aspects of the present disclosure;

FIGS. 7A-7B show an example comparison of a baseline patient havingasynchrony and LBBB (FIG. 7B) and a patient without asynchrony (FIG.7A), consistent with various aspects of the present disclosure;

FIGS. 8A-8B show an example comparison between a patient with leftbundle branch block (LBBB) without resynchronization (FIG. 8A) and withresynchronization (FIG. 8B);

FIGS. 9A-9B show an example comparison between a patient with LBBB andimplanted resynchronization device, consistent with aspects of thepresent disclosure, without capture in the left ventricle (FIG. 9A) andwith capture the left ventricle (FIG. 9B);

FIG. 10 shows an example flow diagram of VV interval optimization usedin CRT (or Biventricular) devices, where the algorithm finds VV_(min),meaning the VV interval that minimizes the asynchrony index IEAI, inaccordance with various aspects of the present disclosure;

FIGS. 11A-11D show an example of sweeping AV delays in order to find theone producing the highest pulse wave amplitude, during right ventricularpacing in VDD (FIGS. 11A-11B) and DDD (FIGS. 11C-11D) modes, consistentwith various aspects of the present disclosure;

FIG. 12 shows a summary of the results obtained in a series of caseswhen sweeping AV delays in order to find the one producing the highestpulse wave amplitude, during RV pacing in the VDD and DDD modes, inaccordance with various aspects of the present disclosure;

FIG. 13 shows an example flow diagram of AV interval optimization bypulse wave amplitude (PWP) in pacemakers programmed to VDD and DDD modes(left and right respectively), consistent with various aspects of thepresent disclosure;

FIG. 14 shows an example of AV and VV interval optimization, bycombining the examples provided in FIG. 12 and FIG. 13, in accordancewith various aspects of the present disclosure;

FIG. 15 shows an example of a possible interface implementation,currently implemented in a prototype apparatus showing multiplefeatures, consistent with various aspects of the present disclosure;

FIG. 16 shows examples of the ten curve types and IEAI ranges in whichwe have classified clinical patients when D1 and D2 are lead II and V6,consistent with various aspects of the present disclosure;

FIG. 17 shows an example flow diagram of how to use some of theembodiments of the present disclosure to optimize the therapy deliveredto a patient that doesn't have baseline asynchrony (IEAI <0.4 and curve1 from FIG. 16), but may be indicated for a pacemaker or defibrillatorimplantation, consistent with various aspects of the present disclosure;

FIG. 18 shows an example flow diagram of how to use some of theembodiments of the present disclosure to optimize the therapy deliveredto a patient that has some asynchrony (0.41<IEAI<0.70 and curve type 3or 9 in FIG. 16) and may be indicated for a pacemaker or defibrillatorimplant, consistent with various aspects of the present disclosure;

FIG. 19 shows an example flow diagram of how to use some of theembodiments of the present disclosure to optimize the therapy deliveredto a patient that has asynchrony (IEAI >0.71 and curve type 6 in FIG.16), and may be indicated for a device implant, consistent with variousaspects of the present disclosure;

FIG. 20 shows an example flow diagram of how to use some of theembodiments of the present disclosure to optimize the therapy deliveredto a patient that has baseline asynchrony (IEAI >0.71 and curve type10), and may be indicated for a device implant, consistent with variousaspects of the present disclosure;

FIG. 21 shows an example flow diagram of how to use some of theembodiments of the present disclosure to optimize the therapy deliveredto a patient that already has an implanted pacemaker and asynchrony(IEAI >0.71 and curve type 8) when paced in the right ventricle,consistent with various aspects of the present disclosure;

FIG. 22 shows an example flow diagram of how to use some of theembodiments of the present disclosure to optimize the therapy deliveredto a patient that already has an implanted pacemaker and asynchrony(0.41<IEAI <0.70 and curve type 5) when paced in the right ventricle,consistent with various aspects of the present disclosure;

FIG. 23 shows an example flow diagram of how to use some of theembodiments of the present disclosure to optimize the therapy deliveredto a patient that already has an implanted CRT or CRTD device andasynchrony (IEAI >0.71 and curve type 8) when paced in both ventricles,consistent with various aspects of the present disclosure;

FIG. 24 shows an example block diagram of a possible implementation ofthe asynchrony index (IEAI) calculation and display and how thisinformation set could be shared with a local programmer, a remoteprogrammer, a local or remote server, or a patient management and/ormonitoring box for further processing, analysis, monitoring or action(i.e., reoptimization of the VV delay) triggered by the local or remotesystems with or without the supervision and approval of interveningmedical personnel, in accordance with various aspects of the presentdisclosure; and

FIG. 25 shows an example block diagram where the surface ECG used in thecalculation of the asynchrony index (IEAI) is derived from intracardiacelectrograms available to the implanted device, and this information istransmitted to remote or local programmers, patient management ormonitoring boxes or remote or local servers for further processing,analysis, monitoring or action (e.g., reoptimization of the VV delay)triggered by the local or remote systems with or without the supervisionand approval of intervening medical personnel, in accordance withvarious aspects of the present disclosure.

While the disclosure is amenable to various modifications andalternative forms, examples thereof have been shown by way of example inthe drawings and will be described in detail. It should be understood,however, that the intention is not to limit the disclosure to theparticular embodiments shown and/or described. On the contrary, theintention is to cover all modifications, equivalents, and alternativesfalling within the spirit and scope of the disclosure. In particular,aspects of the present disclosure refer to the minimum set ofelectrocardiographic leads that allow the simplest and most consistentasynchrony index (IEAI) calculation, but it should be obvious to thoseskilled in the art that other standard or non-standard lead combinationscould be used in the derivation of the asynchrony index (IEAI).

DETAILED DESCRIPTION

Aspects of the present disclosure are directed toward a device thatoperates on the surface electrocardiogram (ECG) or on a pseudo-ECGderived from intracardiac electrodes, and/or leads, and/or anyindifferent electrodes from the stimulation device to determineelectrical asynchrony. Currently, one of the only ways to noninvasivelymeasure mechanical asynchrony of the heart is through Tissue DopplerImaging (TDI). The use of this technique implies considerable investmentof capital resources, the incorporation of an echocardiographist in theoperating room and an unacceptable (from the point of view of risk ofinfection, procedure length, operating room (OR), electrophysiology (EP)catheter time, implanting staff time) lengthening of the procedure timewith the associated increase in cost and complexity. Furthermore, thetwisting of the cardiac fibers during heart contraction makes thismeasurement extremely challenging, thus requiring very highly skilledoperators in charge of the imaging and analysis of the data sets. Thus,the determination of asynchrony by various aspects of the presentdisclosure, simplifies the procedure in terms of staff (the sametechnician can make the connections and measurements), patient safety,cost, time and equipment.

Mathematically, the heart can be modeled as a large oscillator.Attempting a more realistic approach, one could say that the right heartand left heart are two oscillators with the same fundamental frequencyand a time lag between them. More specifically, the left heart can besegmented into several coupled oscillators which according to theirlocation will have different time delays or offsets between them stillsharing the same fundamental frequency. Thus, the determination ofasynchrony is subject to the measurement of this delay betweenoscillators in order to place the delay in a range of normality.Therefore, various aspects of the present disclosure utilize crosscorrelation between the signals of two, three, four and up to 8 leads ofthe surface ECG to determine phase differences between leads (this isbecause only 8 are linearly independent). Many combinations are possibleand can provide results; after careful analysis in multiple patients ofthe advantages and disadvantages of the different combinations, we havedetermined that the simple approach of using only two leads allows us toobtain most of the required information without the extra complexity andcost of a more complex setting. For instance, aspects of the presentdisclosure are directed towards an ECG lead with inferior frontal viewand one involving a lateral view. According to the dipolar theory, theleads are projections of the 3D instantaneous electrical vector of theheart onto two different planes; the horizontal and the frontal planes.On each plane, the leads account for the electrical vector projectionsin different directions, defined by the electrode location. Theseprojections show anatomical correlations with specific regions orsegments of the heart. Thus, lead II can provide information related tothe inferior front side, and V5 or V6 can provide data on the side wallof the left ventricle. Therefore, it should not be surprising that thisset of leads provided the best results in an exhaustive testing inpatients of different lead combinations. Nevertheless, other leadcombinations can produce similar results. As a result, aspects of thepresent disclosure can utilize several of various combinations of leads.For particular patients, the invention allows the physician to usehis/her discretion to choose other pairs of leads to track a particularspatial distribution of asynchrony. For instance a simple approach wouldbe to select the earliest and latest onset QRS complexes from the 8linearly independent leads of the ECG (I,II, V1 to V6). Other approacheswill become obvious to those skilled in the art after reading thisdisclosure, for instance using non standard ECG lead configurations,such as vectocardiography configurations. In another embodiment, all 12leads are fed into the system and the system automatically detects thebest set to use for the IEAI calculations, using cross-correlationanalysis between them and finding the set that best represents thespatial distribution of the dispersion of the activation wave-front. Forsimplicity in this disclosure we have only included the analysis andexamples derived from the same pair of standard leads (lead II and V6).This approach has the added advantage of enabling the classification ofthe hundreds of patients we have studied into a limited set ofasynchrony types (or curve types, FIG. 16).

FIG. 1 shows an example simplified diagram of system blocks, consistentwith various aspects of the present disclosure. The first blocks of FIG.1 represent ECG, His and arterial pulse signal measurement, and thenacquisition of those signals in the second block. The third block showspre-processing (e.g., digitization) of the signals in preparation foranalysis, which is shown in the fourth block. After the signals areanalyzed, the results are visualized, as shown in the fifth block.

In certain embodiments, an acquisition block (e.g., acquisitioncircuitry), consistent with various aspects of the present disclosure,includes filtering, conditioning and standard acquisition for signals.The signals are fed to the preprocessing block (e.g., preprocessingcircuitry), which performs the detection and averaging of QRS complexes.Preprocessing operates on both user-selected leads and consists of theQRS complex detection using an algorithm based on Hilbert transform, thesampling of these complexes on a window of typically 150 ms backward and120 ms forward, their alignment and subsequent averaging.

FIG. 2 shows an example schematic of signal preprocessing flow. FIG. 2shows that QRS complexes from both leads are first fed to a filteringblock, then to a detection block, after that they are both fed to asegmentation block, after that they are both aligned in the QRSalignment block and ensemble averaged in the last block with at least 4beats. During the online analysis, the ensemble average was done usingan exponential ensemble averaging approach and during the offlineanalysis the beats selected by the operator were ensemble averaged.

FIG. 3 shows an example breakdown of an analysis block (e.g., analysiscircuitry). In the first block, parameters are extracted from theincoming averaged QRS complexes from D1 and D2, Axis and Amplitude areobtained in block 1, cross-correlation of both leads is performed inblock 2, and finally the power spectrum of the correlation signal isobtained through the Fourier transform (FFT) in block 3.

The complete equation for the calculation of the asynchrony index (IAEI)is as follows:IAEI=Min{1,(a ₁ *abs(T _(shift))+a ₂ *X _(corrwidth) +a ₃/Amp+a₄ *S_(p1) +a ₅*Axis)/C}

Where Amp is an average amplitude, calculated as the mean of the peak topeak amplitudes of the leads D1 and D2. Thus, Amp=(D1 _(pp)+D2 _(pp))/2,where D1 _(pp) and D2 _(pp) are the peak to peak amplitudes of D1 andD2. In other embodiments of the present invention Amp could be selectedto be either the amplitude of D1 or of D2. The values of the IEAImentioned in this disclosure were obtained with our prototype where theamplitude of D2 was selected as the source of Amp (Lead II or DII).

The calculation of the cross correlation shown in FIG. 4 was done asfollows.

Let X be the cross-correlation signal between D1 and D2, both of lengthN:

${X(n)} = {\sum\limits_{\tau = 0}^{2N}\;{D\; 1(\tau)*D\; 2\left( {n + \tau} \right)}}$

T_(shift) is the delay between the two leads measured as the time ofpeak obtained from the cross-correlation signal of D1 and D2:T_(shift)=MaxArg_(n)[X(n)]. X_(corrwidth) is the width of the measuredcorrelation signal to 70% of the peak amplitude of the signalcorrelation. Let X_(wl) and X_(wr) be the first sample points at whichX(n)≦0.7*max[X(n)] to the left and to the right of max[X(n)]respectively. Then, X_(corrwidth)=Arg[X_(wl)]−Arg[X_(wr)]. An examplemeasurement of the correlated signal parameters (T_(shift) andX_(corrwidth)) are displayed in FIG. 4. In accordance with aspects ofthe present disclosure, T_(shift) points to the time of the correlationpeak and X_(corrwidth) to its width (being measured at 30% amplitude ofthe peak amplitude).

The FFT of the correlation signal was calculated as follows.

Let S be the discrete frequency transform of X(n), with a frequencyresolution of 0.293 Hz: S(w)=fft(X(n),4096).

Sp₁ is a spectral power factor, computed as the ratio of the lowfrequency band with respect to the complete frequency band of S(w):

$S_{p\; 1} = \frac{\sum\limits_{0}^{10}\;{S(w)}^{2}}{\sum\limits_{0}^{40}\;{S(w)}^{2}}$

An example of the FFT of the correlation signal and the calculation ofSp1 is shown in the bottom right portion of FIG. 4. Further, Axis is aterm related to QRS morphology. It can operate on the correlationsignal, and can be calculated by the following algorithm, according todifferent combinations of polarity and amplitudes.

a=max([max(D1) abs(min(D1))]); if (a/(min(D1)))==−1 a=−a; endb=max([max(D2) abs(min(D2))]); if (b/(min(D2)))==−l b=−b; end c=a*b;Axis=0; if c<0 Axis=2 else if a<0 Axis=4 end end

The a_(i) values have been empirically fit so that IEAI presentedmaximal correlation with the activation latency recorded with a catheteron the most distal portion of the coronary sinus (CS in FIG. 5B). C is ascaling factor that affects all the terms equally, and 2<C<10.

The numerical values of IEAI mentioned in this disclosure were obtainedusing the following set of values for a_(i): a₁=0.44; a₂=0.00; a₃=1;a₄=0.72; a₅=0.5 and C=6 for a sampling frequency of 1200 Hz per channeland a least significant bit; LSB=1.9531 uV relative to an input from theECG. Min is the minimum function and returns the minimum value itemsseparated by a colon between parentheses.

Example span for the coefficients a_(I) are:

-   -   a₁: 0 ≦a₁≦1    -   a₂: 0 ≦a₂≦1    -   a₃: 1 ≦a₃≦5    -   a₄: 0 ≦a₄≦1    -   a₅: 0 ≦a₅≦1.

Certain aspects of the present disclosure are directed toward anasynchrony index (MAI). The IEAI varies between 0 and 1, with increasingasynchrony values. A value close to 0 shows normal levels of synchronywhile values close to 1 show a pathological asynchrony. Furthermore, wefound that there is a correlation between asynchrony data measured withTissue Doppler Imaging (TDI) and this index IEAI, thereby showingvalidation of various aspects of the present disclosure againstpreviously utilized methods. The correlation between TDI and IEAI isshown in FIG. 5. Additionally, in accordance with various aspects of thepresent disclosure, an algorithm is utilized to automatically ormanually measure the QRS duration either from the QRS complex directlyor from the ensemble averaged QRS waveform (AAQRSC) to assist in pacingsite location.

The asynchrony index (IEAI) changes with the location of the pacing siteor sites (whether it is about a pacemaker or a CRT device), providedthat the different pacing sites (at the programmed VV delay) createdifferences in the underlying level of electromechanical asynchrony. Insome patients, changing the location of the pacing site may not createmeasurable changes in the asynchrony index. For those cases we use theautomatic/manual measurement of the QRS complex (or the AAQRSC)duration. This measurement has been included into our prototype systemand used in our clinical studies, and has been implemented in variousembodiments of the present disclosure. Thus, if no results come from theasynchrony index, a second variable in the narrowing of the QRS complexcan be observed. The automatic measurement of the QRS width followsthese main steps: 1) Bandpass filter at 5-15 Hz to enhance the QRScomplex; 2) Locate the peak of the complex (maximum for R waves andminimum for Qs waves); 3)—Set the peak as a fixed reference and moveforward and backwards to find the point with the maximum derivative inabsolute value (it can be positive or negative); and 4). From that pointon, go further until the derivative (the first difference) drops morethan 30%. The visual output of this block is two calipers marking theonset and end of the QRS complex. Additionally, various embodiments ofapparatuses of the present disclosure measure QRS duration (manually orautomatically). The screen displays three different colors, namely:green for widths less than 100 msec, yellow for values between 100 and120 msec, and red when they are longer than 120 msec. Further, inanother embodiment and to avoid noise from affecting the measurement,the above mentioned measurements of the width of the QRS complex areperformed on the AAQRSC rather than on the QRS complex itself. FIG. 6Ashows a simplified flow diagram describing the implementation of one ofthe embodiments of the present disclosure. This simplified example flowdiagram deals with the most common situation where the changes in leadposition influence the IEAI. If that were not the case or if thephysician has doubts between two or more sites with similar IEAI, thesystem guides the operator to use the QRS width as the decision variablefor equal IEAI. In FIG. 6A a right ventricular implant is shown andfurther described below, consistent with the embodiments of the presentdisclosure. First the physician makes a decision between an apical or aseptal implant based on clinical and technical aspects of the patientand the system to be implanted (for instance an XSTIM system would beimplanted in the septum), in the case of a septal implant the lead isplaced in a first site and the IEAI is obtained along with the curvetype (see FIG. 16), if a curve type 2 is obtained and if the IEAI indexis below 0.4, the physician can stop and implant at that site.Alternatively, the physician could keep on trying more sites to lowerthe index even more, depending on the therapeutic target desired withregards to the level of asynchrony acceptable to the particular patient.We have found that an IEAI value of 0.4 is a reasonable and achievablegoal. If no site is found on the septum that can achieve this targets(curve type 2 and IEAI<0.4) after 5 sites are tested, the algorithmrecommends the implanting physician to then test the apical sites to seeif a curve type 5 with an IEAI <0.55 can be achieved. In our experience,it was possible to find a site in the septum with IEAI<0.4 in mostcases, therefore if the implanter can't find an IEAI lower than 0.4, thesafest alternative is to recommend that they switch to an apicalimplant. Once this set of tests is completed (we have not repeated forsimplicity the 5 tries counter on the apical site, but it is notadvisable to try more than 5 times due to time reasons), and if no sitethat meets the described criteria has been found, the physician needs tomake a decision of the best site to implant the lead based on therelative level of asynchrony found in apical and septal sites testedaccording to the IEAI value measured at those sites and the therapeutictarget required for the patient, if necessary a CRT or XSTIM systemimplant should be considered. FIG. 6B shows a simplified flow diagramfor a biventricular (or CRT or CRTD) implant, it first sends thephysician through the same procedure as for a right ventricular implant(FIG. 6A) and then asks to place the left ventricular lead in a firstposition and start BV pacing until the last possible site is exploredand its IEAI determined. It recommends the lead to be fixed at the sitewith the lowest value of IEAI. FIG. 6C deals with a pacemaker upgradeand follows the same procedure as in FIG. 6A. We have neither included asite counter on the apical site of the diagram, but it should beapparent that one is required and again we recommend 5 sites or less.For best asynchrony results and to use the existing lead, thisembodiment upgrades the existing pacemaker to a CRT or biventriculardevice (with or without defibrillator) and recommends connecting the oldlead to the RV port of the CRT device and the new lead positionedaccording to this IEAI to the LV pacing port. This is especially usefulfor a complete AV block patient because it gives him a back up pacingsite in case there is a threshold increase at the new septal pacingsite. Alternatively an XSTIM device could be used to upgrade theexisting pacemaker.

FIGS. 7A-7B show diagnostic results of application of an apparatus thatis consistent with various aspects of the present disclosure. The firstcase presented is a normal subject with an electric intraventricularasynchrony index of 0.15 (FIG. 7A) versus a subject with a LBBB and anIEAI of 1 (FIG. 7B). The upper left panel of both FIG. 7A and FIG. 7Bshow the surface ECG, and the upper right panel of both FIG. 7A and FIG.7B show averaged QRS complex. The left middle panel of both FIG. 7A andFIG. 7B show the resulting correlation, and the bottom left panels showthe power and phase spectra obtained from the FFT signal correlation.Notice the gap between D1 and D2 in the case of the subject with LBBBcompared to the healthy subject as well as the morphology of thecorrelation signal, which is wide and not centered in the patient withLBBB.

FIGS. 8A-8B show experimental results during the implant procedure of aresynchronization device, consistent with various aspects of the presentdisclosure, in a patient with LBBB. Note the difference between thebaseline state of the patient, completely asynchronous, with an IEAI of1 (FIG. 8A) and the status of the patient with resynchronization turnedon, fully resynchronized with a IEAI of 0.45 (FIG. 8B). A change of axiscan also be observed in the surface ECG, as well as the narrowing of thecorrelation signal and its centering around zero.

FIGS. 9A-9B show experimental results displaying the usefulness of anapparatus of the present disclosure for the follow-up of an implantedpacemaker. For instance, the LV pacing threshold can be higher than theprogrammed pacing amplitude. This situation of LV pacing without capturenullifies the desired resynchronization effect. As a result, theparameters of the resynchronization device can be changed, increasingthe LV pacing output to achieve consistent capture. In FIG. 9A, thestatus of the LV is shown without capture for a patient with LBBB(IEAI=1) while FIG. 9B shows the same patient with this situationcorrected by increasing LV pacing output (IEAI=0.45). Once the pacingsite is determined by utilizing the asynchrony index, the index can befurther used to determine VV delay. FIG. 10 shows a simplified flowdiagram of the VV optimization performed by this invention on abiventricular or CRT pacing device. Basically, the optimum VV delay isthe one that provides the minimum value of the asynchrony index whileVVI pacing at a constant rate, usually 10 bpm above intrinsic rate. Toobtain the optimum VV delay, the device is programmed to VVI pacing modeand both the right (RV) and left ventricular (LV) outputs are enabledand programmed above capture threshold. At that state, the VV space isscanned from RV only pacing all the way to LV only pacing passingthrough the simultaneous biventricular pacing (BV) when both outputs aresent at nearly the same time by the system (for instance separated by azero to a few milliseconds). For each step in VV interval, theasynchrony index is measured and the optimum VV interval is chosen asthe one that gives the minimum asynchrony index. In the case where morethan one interval gives the same index, then the VV interval with thenarrowest AAQRSC is chosen as the optimum interval. This method allowsus to optimize ventricular synchrony independently of the value of theAV delay.

Additionally, in various embodiments, the information from the arterialpulse wave can be used to determine the optimum AV interval.Additionally, multiple embodiments of the present disclosure can utilizean online measurement of arterial blood pressure, which is useful forhemodynamic assessment of optimal AV interval programming indual-chamber pacemakers. As a result of this measurement, AV intervaloptimization in regular standard cardiac pacing and in cardiacresynchronization therapy can be accomplished by varying the AV intervaland simultaneously measuring the resulting arterial pulse pressure for anumber of beats. Our prototype system allows the averaging of anoperator defined number of beats to perform this measurement, anddifferent embodiments use 8 to 64 beats for each AV delay. In stillanother embodiment, a full number of respiratory cycles is averaged toeliminate respiration as a source of variation of arterial pulsepressure. In still another embodiment the respiratory cycle is detectedautomatically by the system using the modulation it produces in thepulse rate and in the pulse amplitude, once the cycle is identified thesystem is automatically set to acquire ECG and pulse pressure data for 2complete respiratory cycles for each AV delay tested. Aspects of thepresent disclosure are directed toward pulse signal improvement withdifferent AV delays by optimizing left ventricular preload.

For example, FIGS. 11A-11D show the pulse pressure for 4 cases, VDDpacing at an AV delay of 50 ms in FIG. 11A, VDD pacing with an AV delayof 100 ms FIG. 11B and the same AV delays for DDD pacing in FIGS.11C-11D. FIG. 11A and FIG. 11C show an AV delay of 50 ms producing aweak pulse amplitude of 38.6 and 41.0 mmHg, for VDD and DDD pacing whileFIG. 11B and FIG. 11D show a (better) AV delay of 100 ms pushed thepulse signal to 51.5 and 43.4 mmHg for VDD and DDD pacing. FIGS. 11A-11Dalso display the pulse wave and the bar next to it shows the pulseamplitude in numbers. The use of the pulse signal can provideoptimization in embodiments of the present disclosure when there is noneor minimal conduction through the AV node (thus the degree of electricalsynchrony does not change with the different AV delays), or when it isdesired to optimize cardiac preload with the AV delay rather thansynchrony. This will also be true for cases where the optimum AV delayis so short that the ventricles are fully captured and there is nofusion between the intrinsically propagated activation through the AVnode and the artificial pacing stimulation. This lack of fusion meansthat the activation dispersion will not be affected by changes in the AVdelay and thus IEAI will remain constant while changing the AV delay atthis short complete capture values. Furthermore, when the optimum AVdelay is inside the range of complete capture with no fusion, AV delayoptimization focuses on achieving the optimum preload for maximumejected volume of the ventricles, while lead position and VV delaysfocus on obtaining the maximum possible level of synchrony of thecontraction. Therefore our invention allows the implanting physician tooptimize both parameters with regards to preload and synchronyindependently in those cases.

FIG. 12 illustrates the different pulse amplitude outcomes for fourdifferent AV delays for VDD pacing and DDD pacing. For most patients,VDD pacing produces better arterial pulse pressure results than DDDpacing. In the experimental results shown in FIG. 12, an AV delay of 150ms and VDD pacing produced the highest pulse wave peak. This is likelydue to the dispersion of the activation wave-front produced byartificially stimulating the atrium during DDD pacing (pacing bothatrium and ventricle(s)) versus the more uniform activation of theatrium that occurs during normal activation with VDD pacing (sensing theatrium and pacing the ventricle(s)).

FIG. 13 illustrates an example calculation for AV interval optimizationin a pacemaker using arterial pulse pressure for optimizing preloadconditions. Aspects of the present disclosure relating to AV intervaloptimization include choosing the rhythm (paced/sinus) that produces thebest arterial pulse pressure (PWP). In this this case we optimize thePWP using an automatic adjustment of AV delay consisting of sweeping theAV interval in VDD mode to optimize the sensed AV interval by means ofthe pulse wave amplitude. In this procedure we also optimize the preloadconditions of the heart by focusing on the maximum ejected volumeproduced using as a surrogate variable for ejection volume the arterialpulse pressure produced by the contraction of the left ventricle. Thesame procedure is then carried out for DDD mode. Further aspects of thepresent disclosure relating to AV interval optimization (not included inthe figure for simplicity) include choosing the rhythm (paced/sinus)that produces the best IEAI; in this case we would be optimizing thesynchrony level by adjusting with the AV delay the degree of fusionbetween the normally propagated activation waveform that comes from theAV node with the artificially triggered activation produced by theright, left and/or both leads.

FIG. 14 shows an example flow diagram for the optimization of a CRTand/or a pacemaker device (or the equivalent devices in adefibrillator). For a biventricular implant we first go through the flowdiagram of FIG. 10, where the optimum VV delay is established, we thenoptimize the AV delay in either VDD or DDD modes or both using theexample flow diagram of FIG. 13.

The optimum AV interval is the one that provides the largest averagearterial pulse pressure. During AV delay optimization, the VV delay isfixed at the one that gave the lowest asynchrony index. Severaldifferent peripheral sensors can be used for the arterial pulse pressuremeasurement: for instance our prototype was implemented using thephotoplethysmographic; the tonometric; and the oscillometric sensors.Other methods should be obvious to those skilled in the art. Themeasurement of the pulse wave provides indications of an optimal AVinterval. This measurement can be utilized in embodiments havingpacemakers or CRT devices. Additionally, the same indicator (pulsesignal) can be used to adjust the VV interval in CRT implantations. Inthis case the operator needs to consider that changing the VV intervalwould change the AV delay, therefore the test should be conducted underVVI pacing at a constant rate, usually 10 bpm above the intrinsic rateshould be adequate. Nevertheless, since VV interval affects mostly thedispersion of the activation wave-front and thus asynchrony the VVinterval should be adjusted using the asynchrony index with the width ofthe AAQRSC as a secondary variable when needed, and not using PWP whichis most sensitive to preload conditions and not necessarily synchrony.When the therapeutic target of asynchrony has been achieved with leadsite and VV delay and therefore it is not required to attempt to tweakthat level with creating a three way fusion between the artificial rightand left pacing induced wave-fronts with the intrinsic activation thatcomes through the AV node, the AV delay should be optimized using thepulse signal. Furthermore, apparatuses, consistent with various aspectsof the present disclosure, can be a tool capable of replacing theplacement of a catheter into the coronary sinus to measure times betweenventricular segments, either for diagnostic procedures or to determinetherapeutic improvements in clinical follow-up.

Furthermore, apparatuses, consistent with various aspects of the presentdisclosure, can be a tool capable of telling the implanting medicalpersonnel that a lead position in one site of the RV or the LV willprovide a more synchronic electromechanical activation of the heart thana lead placed in another site. Furthermore, apparatuses consistent withvarious aspects of the present disclosure using the asynchrony index,the AAQRSC width or any combination of both will enable the implantingphysician to know how far away in terms of asynchrony the particularlead placement achieved is from the therapeutic target that he/she hasfor that patient. Therefore, this enables a decision, during theimplant, to consider other therapeutic options for that particularpatient if the desired therapeutic target cannot be achieved. Aparticular example is a patient undergoing a right ventricular implant,in that case the asynchrony index will enable the implanting personnelto know if the degree of asynchrony being created by the artificialpacing spike in the right ventricle, at the site chosen by the physicianmeets his/her therapeutic target for that patient for not initiating oraccelerating the progression towards heart failure that excessiveasynchrony would trigger. If the physician cannot find an adequate rightventricular lead location, he/she may make the decision to upgrade thepatient to a CRT or an XSTIM device.

Various aspects of the present disclosure are directed towardapparatuses having a self-contained device including a screen. Thisapparatus can be provided with a built-in printer or a connection to aprinter in various embodiments. Further, apparatuses of the presentdisclosure include a device to which the ECG and arterial pulse sensorcables are connected. This device features an output that feeds a laptopcomputer containing the software protected by a software key. Thisdevice (e.g., a processor arrangement having circuitry) is configured tocalculate an index to help find the optimal pacing site for any pacingdevice, with any lead configuration. Further, the device is configuredto provide tools for AV-delay adjustment based on the pulse signalamplitude with application on DDD/VDD pacemakers and CRT devices, eitherautomatically or manually. The device is also configured with tools forVV-delay adjustment based on the asynchrony index and/or the pulsesignal amplitude with application on DDD/VDD pacemakers defibrillatorsand CRT and CRTD devices, either automatically or manually. Further, thedevice is configured to calculate an index to mark electricalintraventricular dyssynchrony in patients without pacemakers. Thedevice, consistent with various aspects of the present disclosure, canalso be configured to calculate an index to mark electricalintraventricular dyssynchrony in patients with pacemakers, and todetermine candidates who will potentially benefit from CRT therapy.Additionally, the device is configured to allow the follow-up ofpatients implanted either with pacemakers or CRT devices, and can beintegrated into a commercially available pacemaker, defibrillator or CRTdevice, or alternatively inside one of their programmers. Additionally,the device could transmit the information through radio frequency,through a network or using a standard or proprietary protocol to anymeans of remote devices, for instance a local server in the hospital ora remote server at a health care center where the follow up of thepatient is done, or to a remote server of the manufacturer of the devicebeing implanted for remote patient monitoring, follow up and/ormanagement. The implanted device could be programmed to cycle through VVintervals or AV intervals inside a safety range pre-determined by theresponsible medical personnel and the asynchrony index results could bederived inside the device using a calculated ECG from intracardiacelectrograms, or transmitted to the remote devices and calculated in anexternal system. The resulting information could then be used torecommend an update of the VV or AV interval as the patient's conditionevolves with time. This update could be programmed directly into theimplanted devices through the communications protocol available or beinformed to the responsible physician for update at the next follow up.Many alternatives and variations of this approach should be obvious tothose skilled in the art.

Various embodiments are directed towards an apparatus consistent withaspects of the present disclosure combined inside a pacemaker or CRT orCRTD (CRT plus defibrillator) or pacemaker plus defibrillator. In theseembodiments, ECG information can be obtained, processed, and displayed.Therefore, modification of the software of a pacemaker or CRT or CRTD(CRT plus defibrillator) or pacemaker plus defibrillator device can bemade to implement various aspects of the present disclosure. Tweaks andadjustments to the front end filters, digitalization rates and digitalsignal processing capabilities can be made.

Additionally, apparatuses of the present disclosure, in variousembodiments, can be implemented (without the His or the arterial pulsecapabilities) inside the software of the pacemaker CRT or CRTD (CRT plusdefibrillator) or pacemaker plus defibrillator. In these instances, theECG is replaced by a pair of leads formed by the available electrodes inthe defibrillator, pacemaker, CRT or CRTD device that best resembles asa pseudo ECG lead (such as Lead II and V6), or a representation of theinferior frontal side and the lateral wall of the left ventricle.

Further, an asynchrony index (IEAI), consistent with various aspects ofthe present disclosure, is implemented in an iPad®, iTablet®, or smartphone (e.g., a smart device). The ECG information is gathered byseparate hardware, sent to the smart device through blue tooth, WiFi,WiMax, G3, G4, G5 or other cellular protocol and then processed anddisplayed by the smart device. The smart device can also store theinformation on the Cloud for people to keep a record of their asynchronyindex or for physicians or care providers to monitor the patient'shealth status or adjust their therapy, including drug adjustments. Thiswill make a diagnosis of asynchrony much easier and allow for earlierinterventions (diet, lifestyle, stress, tobacco, etc.) that may even beable to prevent and preempt the need of device implantation to correctit. Since it is reasonable and even expected that the morphology andstatus of the patients heart will change with time after the officevisit, the device could be allowed to automatically try different VV orAV intervals (small changes pre-programmed by the intervening medicalpersonnel) and report the information on the asynchrony index,information that could be further used to reprogram the baseline valueof the VV or AV delay of a CRT device remotely or locally with physicianor medical personnel approval once a recommendation is made by thedevice. Furthermore, the ECG hardware could be miniaturized and attachedto the patient temporarily or chronically either subcutaneously or onthe skin, directly or through a special shirt or underwear, equippedwith disposable or rechargeable batteries and communicate through lowpower blue tooth or other communication protocol with the externalsystem that may fully reside inside an iPad, tablet or smart phone orsimilar device. The external device could act as the display unit or asa full processing unit calculating the index by itself or remotely inthe cloud or both. The data could be stored locally or on the cloud.

Various embodiments of the present disclosure are directed towardacquiring data from an ECG, and to providing the data for analysis by apatient or health care specialist. The ECG data can be acquired locally(e.g., in the physician's office, patient's home, ambulance, hospital,ambulatory) and transmitted to a remote location. In this manner, anynumber of physicians/nurses/technicians can analyze the data acquired(assuming appropriate authorization is given). For instance, a datainterface can be used to upload the ECG data to a remote device. Apatient or health care specialist can then review the data. Thisreviewed data can be used in developing a program of VV or AV delaysthat minimizes asynchrony, which can include additional treatmentoptions, and/or adjustments. Information other than, or in addition to,ECG data can also be acquired and uploaded.

Furthermore, certain embodiments contemplate that for devices withactivity sensors a correlation can be made between the optimum VV or AVintervals during different levels of activity such that a table could becreated inside the device that would allow the adaptation of the VV orAV interval to the level of activity measured. Activity sensors can beof several types, from minute ventilation sensors that track the changein respiratory activity created by exercise to simple accelerometersensors that track changes in acceleration in one or multiple axis. Instill another embodiment the sinus rate detected by the atrial lead isused to gage the activity level and correlate the optimum VV or AVinterval with the heart rate at which the optimization occurred. Allthese analysis can be performed inside the device or outside theimplanted device by an external system that could return the recommendedprogramming to the device in a simplified format, i.e. a table withsensed atrial rates and optimum VVs or AVs for each rate range, for theimplanted device, such external analysis will minimize the devicehardware/firmware requirements and power consumption.

Certain embodiments contemplate a wired interface for uploading theinformation. The interface can include one or more standardizedinterfaces (e.g., USB or Firewire) or proprietary interfaces. Forexample, the system can include a USB circuit that is configured tooperate as a USB peripheral device. A USB cable, with USB connectors,can connect the system to a remote processing device (e.g., a laptopcomputer, tablet computer or personal computer). The acquired data canbe automatically uploaded using software drivers and/or the system canappear as a storage device (e.g., flash drive) upon which the acquireddata is stored.

Various embodiments are directed toward a wireless interface foruploading of the acquired data. The wireless interface can be configuredfor use with various standardized protocols (e.g., Bluetooth, IEEE802.11xx, cellular protocols, near field communications, far field RFcommunications or WiMax). In certain embodiments, the wireless circuitfor the interface can be configured to conserve power by powering downor entering a low power state between uploading, like low powerBluetooth or its power saving schemes.

Consistent with one or more embodiments, access to the acquired data canbe limited to authorized persons. This can include, for example, the useof encrypted communications and/or password protection.

Consistent with one of more embodiments the device can be completelyimplemented either inside an ECG machine or inside a programmer forpacemakers, defibrillators and/or CRTD devices.

FIG. 15 shows an example interface of an apparatus, consistent withvarious aspects of the present disclosure, showing a feature to measureQRS durations. The upper panel shows two sets of calipers marking thestart and end of both QRS complexes. The calipers can be turned on oroff by selecting the correct option in the drop down menu above the ECGwindow. The update time selects the interval between new readings of theIEAI index and other variables displayed. The number of beats averagedwindow indicates the number of beats that have been used to calculatethe average value of the pulse pressure. This number is represented bythe green bar at the bottom right of the window. The large red number inthe top right side is the IEAI 0.77. Right beneath the IEAI are theselection buttons for the source of Amp in the IEAI equation. For theIEAI numbers reported in this disclosure we have used the “lead II”selection. The drop down menu on the top right is the filter settingselector. The preset analysis time determines the time sample of the ECGand pulse pressure used for the analysis. The QRS detection triggerdefines what lead D1 or D2 is used for the detection of the complex. Thewaveform in the top right window is the Cross-correlation between D1 andD2. The waveforms in the top left window are the QRS complexes of the D1and D2 leads (in this case lead II and V6). The numbers underneath arethe QRS widths DII in green 93 ms because it is below 100 ms and V6 inred 128 ms because it is over 120 ms. The drop down selection menuunderneath these readings selects the type of sensor used for theacquisition of the arterial pressure waveform. Finally in the bottomcenter of the window you find the arterial pressure waveform. It shouldbe obvious that those skilled in the art could come up with a myriad ofother possible display interfaces that would still be covered by thisinvention.

An example of the patient classification that can be performed using theD1 and D2 curves and the IEAI number is shown in FIG. 16 for theparticular coefficients a_(i), C, sample rate, etc. described in thepresent disclosure as used in our prototype system. The differentcolumns cover the following classes: 1) Synchronous (0≦IEAI≦0.4); 2)Intermediate (0.41≦IEAI≦0.70); and 3) Asynchronous) (0.71≦IEAI≦1). Theintermediate patients are further subdivided into a) normal conductionwith and without right bundle branch block (RBBB) and b) left anteriorbranch hemi block (LABH) with and without right bundle branch block(RBBB). The asynchronous patients are divided into the left bundlebranch block (LBBB) and the LABH with and without RBBB. For each columnwe have three rows, in the first row we depict the curves for baselinerhythm (no pacing), which create curve type 1 for the synchronous type,curve 3 for the intermediate type with normal conduction with andwithout RBBB, curve 9 for the intermediate type with LABH with orwithout RBBB, curve 6 for the asynchronous type with LBBB and curve 10for the asynchronous type with LABH with or without RBBB. The second rowcorresponds to the conventional CRT therapy (biventricular pacing),which creates curve 4 for the intermediate column and corresponds tooptimized CRT therapy and for the asynchronous column, the non-optimalCRT creates curve 7. The third row is for pacemakers, curve 2 is createdby septal stimulation, curve 5 (intermediate) and curve 8 (asynchronous)are created by apical stimulation.

FIGS. 17 to 23 summarize in a simplified flow diagram the process ofdiagnosis and application for each diagnosis of the different algorithmsmentioned in the present disclosure. FIG. 17 corresponds to patientswith no asynchrony and curve type 1. If they are indicated for apacemaker implant then the diagram indicates that the lead selectionprocess described in FIG. 6A should be used, followed by the AV delayoptimization procedure described by FIG. 13. FIG. 18 applies to patientswith curve types 3 or 9 and some asynchrony. The diagnosis would bedifferent but the approach to follow the same as in FIG. 17. Thesimplified diagram of FIG. 19 contemplates the implantation of a leftventricular lead thus flowing through the RV lead implant optimization(FIG. 6A) followed by the LV lead site optimization (FIG. 6B), the VVoptimization (FIG. 10) and the AV delay optimization (FIG. 13). The flowfor FIG. 20 despite different diagnosis than FIG. 19 ends up with thesame procedure as in FIG. 19.

The case for a patient that has an existing implanted lead and pacemakerwith curve 8 during pacing and asynchrony is depicted in FIG. 21. In thecase where the patient also has asynchrony (curves 6 or 10) at baseline(without pacing) the flow ends up with the upgrade to a CRT device withleft and right ventricular pacing. The patient could also be indicatedan XSTIM device in lieu of a CRT device. If the patient baseline is notasynchronous, then a septal lead position for the RV is recommended plusa CRT device with the septal lead connected to the LV port of the CRTdevice and the old lead connected to its RV port, or an XSTIM device.

Alternatively, in the cases of FIGS. 17 to 21, a pacemaker using highvoltage output to stimulate the His bundle and bypass the conductionblock, similar to those described by patents U.S. Ser. Nos. 00/751,2440,00/800,5544, 00/801,4861 and 00/805,0756 and applications 20120101539could be utilized (XSTIM). In this last case the IEAI will allow theoperator to detect when the His bundle position is achieved since itsvalue will drop to near zero and the curve type would be 1. And only theRV site optimization flow diagram of FIG. 6A or 6C could be used withthe lead on the septal side. In this case the target site is known, theHis bundle, and the IEAI could be used to confirm it has been located.

FIG. 22 contemplates a patient that has an existing pacemaker and leadimplanted and intermediate asynchrony with curve type 5 while paced inthe ventricle (Vpaced). For this case only the AV delay optimizationalgorithms of FIG. 13 would be used.

Finally, the case where a CRT device is implanted and pacing both rightand left ventricles (BV) in a non-optimized way is described by FIG. 23,where a patient with asynchrony and curve 7 while BV paced iscontemplated. For this patient, the VV delay optimization algorithm ofFIG. 10 is used first and then the corresponding AV delay optimizationalgorithms of FIG. 13.

FIG. 24 shows an apparatus connected to a patient to extract the ECGthrough leads or some form of telemetry from a device attached to thepatient or implanted subcutaneously. The information is then sent to anamplifier having an output which drives an optional analog to digitalconverter for presenting the approximated signal to asoftware-programmed processor (e.g., CPU) where the signals areconditioned and analyzed and the IEAI extracted. In certain embodiments,the least significant bit of the output signal from the A/D(analog-to-digital) converter refers back to the voltage of the input ofthe ECG amplifier. The specific (amplifier) gain can vary, for example,relative to the A/D settings. In one such embodiment, the leastsignificant bit of the A/D (analog-to-digital) converter represents1.9531 microvolts at the input of the amplifier. The bandwidth can beinferred from the sampling rate of 1200 Hz. Finally the information issent to an optional display. Optionally also the information could besent to a local programmer, a remote programmer, a local or a remotepatient monitor box or a remote or local server for processing,analysis, monitoring, follow up, patient management or analysis. Thisanalysis could lead to a table of values of VV or AV delay versusactivity that could be further loaded or programmed back into animplanted pacing device. Alternatively this analysis could lead to atable of values of VV or AV delays versus heart rates that could befurther loaded or programmed into the device to create a rate responsiveVV or AV delay setting or mode. The IEAI information could be used tohelp monitor the heart failure status of the patient, to help adjustdrugs, such as diuretics, beta blockers or digitalis remotely bymonitoring the changes they produce in the level of asynchrony.

FIG. 25 shows the case where the ECG information is obtained by animplanted device or by the implanted pulse generator (pacemaker, CRT ordefibrillator or combination of them) and transmitted through somewireless protocol to an optional external processor and display unit orto a remote or local programmer or remote or local patient monitor boxor remote of local server for further processing, analysis, use inpatient management, monitoring or to provide the physician or attendingmedical personnel information about the changes in the asynchrony levelthrough the IEAI obtained. Furthermore, in an embodiment of the presentinvention, the implanted device sends the ECG information andcorresponding VV or AV value, for different values of VV or AV delaythat are automatically changed in a range predefined by the responsiblemedical personnel, the external devices calculate the IEAI values foreach VV or AV value. This information is then fed back to theresponsible medical personnel and/or to the device in the form of atable or programming change that allows the device to update the VV orAV delay at which it operates when the optimum VV or AV delay isdifferent from the one that was programmed in the last follow up, forinstance due to a change in the conditions of the patient. Furthermore,this VV or AV delay changes could be made at different HR or activitylevels (as measured by the rate responsive sensors the devices may have)and the information compiled in the external devices in such a way as tofed back to the responsible medical personnel and/or the device a tableor programming change that allows the device to adapt the VV or AV delaywith the HR and/or activity level of the patient in such a manner as todynamically optimize the VV or AV delay.

Aspects of the present disclosure allow for the evaluation ofintraventricular electrical asynchrony showing an excellent correlationwith Doppler echocardiography and Tissue Doppler Imaging. It is usefulfor evaluating candidates for electrical resynchronization therapy tooptimize the site of implantation of these devices, to improvepost-implant follow-up as well as adjusting the AV and VV intervalsettings when programming the devices.

Various modules may be implemented to carry out one or more of theoperations and activities described herein and/or shown in the Figures.In these contexts, a module (or illustrated block or box) is a circuitthat carries out one or more of these or related operations/activities.For example, in certain of the above-discussed embodiments, one or moremodules are discrete logic circuits or programmable logic circuitsconfigured and arranged for implementing these operations/activities, asin the circuit modules shown in the Figures. In certain embodiments, theprogrammable circuit is one or more computer circuits programmed toexecute a set (or sets) of instructions (and/or configuration data). Theinstructions (and/or configuration data) can be in the form of firmwareor software stored in and accessible from a memory (circuit). As anexample, first and second modules include a combination of a CPUhardware-based circuit and a set of instructions in the form offirmware, where the first module includes a first CPU hardware circuitwith one set of instructions and the second module includes a second CPUhardware circuit with another set of instructions.

Certain embodiments are directed to a computer program product (e.g.,nonvolatile memory device), which includes a machine orcomputer-readable medium having stored thereon instructions which may beexecuted by a computer (or other electronic device) to perform theseoperations/activities.

In still another embodiment the implanted device calculates the IAEIusing intracardiac electrical information and tracks the changes in IAEIthat occur with exercise and stress, those changes are stored and theirrange of change established. The device then maps the range of IEAIchanges with exercise to the maximum sensor rate minus the baselineheart rate programmed by the implanted physician, in such a way thatwhen the IAEI is at the lowest bound the pacing rate is increased to themaximum sensor rate.

Based upon the above discussion and illustrations, those skilled in theart will readily recognize that various modifications and changes may bemade to the present disclosure without strictly following the exemplaryembodiments and applications illustrated and described herein.

What is claimed is:
 1. An apparatus comprising: an acquisition circuitconfigured and arranged to collect a first signal at a first location ofa subject's heart and a second signal at a second location of thesubject's heart, the first signal being indicative of at least one of afirst heart surface electrocardiography (ECG) and a first intracardiacelectrogram (EG), and the second signal being indicative of at least oneof a second heart surface ECG and a second intracardiac electrogram(EG); preprocessing circuitry configured and arranged to performdetection and filtering of QRS complexes of the first signal and thesecond signal collected by the acquisition circuit; analysis circuitryconfigured and arranged to: from the first signal and the second signal,extract signal information comprising one or more of parameters and datapoints, segment the QRS complexes of the first signal and the secondsignal using the extracted information, cross-correlate the QRS complexsegments of the first signal and the second signal to produce acorrelation signal, and provide an asynchrony index that at least one ofis based on and corresponds to the correlation signal and that indicatesa level of electrical asynchrony between the first location and thesecond location.
 2. An apparatus according to claim 1, furthercomprising intracardiac electrodes, coupled to the acquisition circuit,configured and arranged to collect the first signal and the secondsignal, and to stimulate the subject's heart.
 3. An apparatus accordingto claim 1, wherein the analysis circuitry is further configured andarranged to determine whether the asynchrony index is conclusive, and inresponse to the asynchrony index being inconclusive, measure the QRSwidth by performing one of the following: bandpass filter the firstsignal and the second signal at 5-15 Hz to enhance the QRS complex; andlocate the peak of the complex via determining a maximum for R waves andminimum for Q-S waves.
 4. An apparatus according to claim 1, wherein theextracted information comprises timing of the QRS complex by detectionof R or S waves, the correlation signal comprises at least one ofTshift, which comprises a delay between peak obtained from thecorrelation signal, or Xcorrwidth, which comprises a width of thecorrelation signal, and the analysis circuitry is further configured andarranged to extract the parameter Tshift from the correlation signal asa measure of time displacement between an activation of the two surfacesof the heart collect from the first signal and the second signal.
 5. Anapparatus according to claim 1, wherein the analysis circuitry isfurther configured and arranged to extract Xcorrwidth, which comprises awidth of the correlation signal, from the correlation signal as ameasure of difference in shape between the first signal and the secondsignal.
 6. An apparatus according to claim 1, wherein the analysiscircuitry is further configured and arranged to calculate a FourierTransform or a fast Fourier Transform of the correlation signal betweenthe first signal and the second signal.
 7. An apparatus according toclaim 1, wherein the analysis circuitry is further configured andarranged to calculate an energy ratio of a low frequency band of thecross-correlation signal relative to a total energy of the correlationsignal energy spectrum.
 8. An apparatus according to claim 1, whereinthe extracted information comprises information regardingvectocardigraphical data, and wherein the asynchrony index is zero ifthe vectocardigraphical data is normal, and the asynchrony index ismaximal when the vectocardigraphical data is maximally abnormal.
 9. Anapparatus according to claim 1, wherein the analysis circuitry isfurther configured and arranged to increase the asynchrony index by afirst predetermined factor when both signals have opposite to normalpolarities, to increase the asynchrony index by a second predeterminedfactor, that is less than the first predetermined factor, when the firstand second signals have different respective polarities in that one isnormal and the other is abnormal.
 10. An apparatus according to claim 1,wherein the extracted information comprises at least one of amplitudesof the QRS complexes, and a mean or average of peak-to-peak amplitudesof the QRS complexes.
 11. An apparatus according to claim 1, wherein theacquisition circuit is further configured and arranged to collect thefirst signal and the second signal as corresponding to the first EG andthe second EG.
 12. An apparatus of claim according to claim 1, whereinthe acquisition circuit is further configured and arranged to collectthe first signal and the second signal as corresponding to the first ECGand the second ECG.
 13. An apparatus according to claim 1, furthercomprising: an implantable device configured and arranged to cyclethrough at least one of one or more interventricular delay (VV)intervals and one or more atrio-ventricular (AV) intervals inside apre-determined safety range and to calculate electrograms, theelectrograms comprising the first intracardiac electrogram and thesecond intracardiac electrogram, obtained by the device duringimplantation; and the analysis circuitry further configured and arrangedto determine the asynchrony index of the subject based on one or more ofthe electrograms.
 14. An apparatus according to claim 13, furthercomprising: the analysis circuitry configured to determine the AV delayinterval associated with a lowest one of the determined synchronyindices as the optimal AV delay interval.
 15. An apparatus according toclaim 13, further comprising: the analysis circuitry further configuredto determine the VV delay Interval associated with a lowest one of thedetermined synchrony indices as the optimal VV delay interval.
 16. Anapparatus according to claim 15, further comprising: an arterial pulsepressure sensor configured to measure arterial pulse pressure of thesubject; and the analysis circuitry configured to determine one of theAV intervals as the optimal Av interval based on the arterial pulsepressure measured in response to the cycling of that AV interval,wherein the implantable device maintains the optimal VV interval as theVV interval that minimizes the asynchrony index while cycling throughthe AV intervals to select the optimal interval.
 17. An apparatusaccording to claim 16, further comprising: the analysis circuitryfurther configured to average the measured arterial pulse pressure foreach of the cycled AV intervals, wherein the optimal AV interval isassociated with the largest average arterial pulse and the lowestasynchrony index simultaneously occurring at any of the AV intervalswhen compared to the average pulse pressures and asynchrony indexes forthe remaining AV intervals.
 18. An apparatus according to claim 16,further comprising: the analysis circuitry further configured to averagea full member of respiratory cycles of the subject to eliminate thesubject's respiration as a source of variation of the measured arterialpulse pressure.
 19. An apparatus according to claim 13, wherein theimplantable device is at least one of a pacemaker and a cardiacresynchronization therapy device.
 20. An apparatus according to claim 1,further comprising circuitry that is communicatively coupled with theanalysis circuitry and that is used to provide a based on the asynchronyindex a pacing change of a device configured and arranged to beimplanted in the subject.